We are investigating the function of Cbl proteins, a family of proteins that regulate tyrosine kinase activity. Cbl proteins belong to the RING finger class of ubiquitin protein ligases (E3s) and function as E3s for activated tyrosine kinases. My group cloned two of the three mammalian Cbl genes (Cblb and Cblc) and demonstrated that all mammalian Cbl proteins mediate ubiquitination and degradation of the activated epidermal growth factor receptor (EGFR) as well as other components of the signaling complex. Ongoing work is focused on understanding the biochemical and physiologic functions of the three mammalian Cbl proteins in epithelial cells and elucidating the differences in their specificity and/or function. We have been focused on the function of Cblc, the most recently identified family member about which the least is known. This protein is expressed only in epithelial cells and my group is particularly interested in epithelial malignancies such as breast cancer. Previously, to understand the function of the Cblc protein, we collaborated with Josef Penninger (IMBA, Vienna, Austria) to knock out Cblc. Unfortunately, the Cblc null mice have no detectable abnormalities. To gain insight into the function of Cblc, we have used yeast two-hybrid screens to detect novel proteins that interact with Cblc. Currently, we are characterizing the function of these proteins and the consequences of their interactions with Cblc. In addition, we have identified mutations in Cblc that is predicted to create a transforming version of Cblc from a murine breast cancer. We are investigating this mutant in more detail to see if it is transforming and searching for evidence of other mutants in murine and human tumors. More generally, ongoing work is characterizing the molecular mechanism by which the Cbl proteins mediate ubiquitination. This includes investigating the structure-function relationship of the Cbl proteins, and their interactions with the ubiquitin conjugating (E2) proteins. We have collaborated with the Randazzo group (CCR)to investigate the interaction between ARAP1, Cbl protiens, and EGFR trafficking. In addition we are collaborating with Marcus Clark (University of Chicago) to study the role of Cbl-b on B-Cell antigen receptor trafficking and with Jian Zhang to understand the function of Cbl-b in T-cell receptor signaling. Finally, we have an ongoing collaboration with Allan Weissman (CCR) on the general investigation of mechanisms by which the Cbl proteins function as E3s. Overall, these studies should provide insight into the biochemical, biological, and pathophysiological functions of the Cbl proteins.